Derivatives of 3-aryl-5-alkylhydantoins

ABSTRACT

3-Phenyl-5-alkylhydantoins and certain derivatives thereof are anti-inflammatory, analgesic and antipyretic agents and are prepared through cyclization of a phenylhydantoic acid or ester. A typical embodiment is 3-(p-fluorophenyl)-5-methylhydantoin.

United States Patent Field of Search ..260/309.5

Gruenfeld 5] July 11, 1972 e [54] DERIVATIVES 0F 3-ARYL-5- [56]References Cited ALKYLHYDANTOINS UNITED STATES PATENTS [72] Inventor:Norbert Gruenfeld, Bronx, NY. 3,134,663 5/1964 Kroll ..260/309.52,075,359 3 1937 S 12b ..424 250 {73] Assignee: Ciba-Geigy Corporation aerg 22 Filed: Feb. 27, 1970 OTHER PUBLICATIONS Chem. Abstracts, Vol, 60:14512 f June 1964, Imperial [21] App1.No.: 15,208 Chemical Industries,Ltd.

Related Application Data Primary Examinerl-lenry R. J iles [63]Continuation-impart of Ser. No. 717,035, March 28,ASSiS'a'1'EX1miMP4-D-wlmers 1968, abandoned Attorney-Karl F. Jorda andBruce M. Collins 52 us. Cl. ..260/309.5, 424/273, 260/515 A, [57]ABSTRACT 260/515 R, 260/521 R 3-Phenyl-5-alkylhydantoins and certainderivatives thereof 51 lm. C1. ..C07d 49/32 are anti-inflammatory,analgesic and antipyretic agents and l 58] are prepared throughcyclization of a phenylhydantoic acid or ester. A typical embodiment is3-(p-fluoropheny1)-5-methylhydantoin.

6 Claims, No Drawings 1 DERIVATIVES OF 3-ARYL-5-ALKYLIIYDANTOINS CROSSREFERENCE This is a continuation-in-part of Ser. No. 717,035 filed Mar.28, 1968, now abandoned.

DETAILED DISCLOSURE The present invention pertains to certain novelderivatives of 3-phenyl-5-alkylhydantoins, in particular to compounds ofthis class which have the structural formula:

in which R is (lower)alkoxy, fluoro or trifluoromethyl and R is(lower)alkyl.

The present invention also pertains to the use of these and other3-phenyl-5-alkylhydantoins as antiinflammatory, analgesic andantipyretic agents and to pharmaceutical compositions in unit dosageform adapted for realization of these utilities.

Throughout this specification and the claims, the term (lower)alkyldenotes a branched or straight monovalent hydrocarbon group of from oneto four carbon atoms such as methyl, ethyl, propyl, isopropyl and thelike, preferably the lowest member, methyl. Similarly the term(lower)alkoxy" denotes ether derivations of such (lower)alkyl groups,such as methoxy, ethoxy, propyloxy and the like, the preferred speciesagain being the lowest member, methoxy.

The present method of treating inflammatory conditions, pain and feverin animalscomprises the oral administration to the animal of aneffective amount of a compound of the formula:

in which R" is (lower)alkoxy, fluoro,

hydrogen or (lower)alkyl and R is (lower)alkyl.

The present invention also provides pharmaceutical compositions for thepractice of this method. These compositions provide a unit dosage of acompound of Formula II in combination with a pharmaceutical carrier, theamount being sufficient to effect an anti-inflammatory, analgesic and/orantipyretic response upon a single or multiple dose regimen.

The 3-phenyl-S-alkylhydantoins of Formulas I and II can be preparedsynthetically through initial condensation of an amino acid or an alkylester thereof of Formula III, generally as an acid addition salt, and aphenylisocyanate of Formula IV and cyclization of the resultingphenylhydantoic acid or ester thereof.

trifluoromethyl, chloro,

III IV NZCNH wherein R" and R are as defined above and R is hydrogen or(lower)alkyl.

Thus for example, equimolar amounts of D-, I.-, or l),l.- alanine methylester, an appropriately substituted phenylisocyanate and a base such assodium bicarbonate are heated in the presence of an inert nonaqueoussolvent such as benzene. The resulting methyl phenylhydantoate,alternatively named as N,-phenyl-N -(2-propionic acid methyl ester)urea,is isolated, preliminarily purified, hydrolyzed with acid or base, andthen cyclized in the presence ofa mineral acid. The product is isolatedby simple filtration and purified through conventional methods such asrecrystallization.

The 3-phenyl-5-alkylhydantoins of the present invention exist as opticalisomers and both the racemates and the individual isomers are within thescope of the present invention. While the racemate is generallyemployed, the individual isomers can be obtained through use of thecorresponding optical isomer of the amino acid starting material.

The 3-phenyl-5-alkylhydantoins of Formula II are useful for thetreatment of inflammatory conditions such as dermatitis, inflammation ofjoints and similar conditions which are usually responsive to knownantiinflammatory agents. They are also useful in the treatment of painand in reducing hypernormal body temperatures. They are well toleratedand do not appear to cause undesirable side effects such as allergicreactions. A particularly preferred compound is3-(p-fluorophenyl)-5-methylhydantoin.

Administration is effected via the oral route. For this purpose, a3-phenyl-5'alkylhydantoin of Formula II is incorporated in compositionssuitable for oral administration to animals in solid and liquid unitdosage forms, such as tablets, capsules, powders, granules, syrups,elixirs and the like. The term unit dosage form as used in thisspecification and claims refers to physically discrete units suitable asunitary dosages for animals, each unit containing a predeterminedquantity of active material calculated to produce the desired effect inassociation with the required pharmaceutical diluent, carrier orvehicle.

Powders are prepared by comminuting a B-phenyl-S-alkylhydantoin ofFormula II to a suitable fine size and mixing with a similarlycomminuted diluent, The diluent can be an edible carbohydrate materialsuch as starch. A sweetening agent or sugar may also be present as wellas flavoring oil.

Granules for reconstitution into a liquid oral preparation are preparedutilizing water-soluble diluents. A powder mixture of the finely dividedcompound and a water-soluble diluent such as sucrose, glucose, and thelike, is wetted with a binder such as acacia mucilage, gelatin solution,methylcellulose solution and forced through a screen to form granuleswhich are allowed to dry. A suspending agent such as tragacanth may beincluded in the composition.

Capsules are made by :preparing a powder mixture as described above andfilling formed gelatin sheaths. As an adjuvant to the filling operation,a lubricant such as talc, magnesium stearate and calcium stearate may beadded to the powder mixture before the filling operation.

Tablets are made by preparing a powder mixture, granulating or slugging,adding a lubricant and pressing into tablets. The powder mixture isprepared by mixing the compound, suitably comminuted, with a diluent orbase such as starch, sucrose, kaolin, dicalcium phosphate and the like.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste or acacia mucilage and forcing through a screen. Asan alternative to granulating, the powder mixture can be slugged, i.e.,run through the tablet machine and the resulting imperfectly formedtablets broken into slugs. The slugs can be lubricated to preventsticking to the tablet forming dies by means of the addition of stearicacid, a stearate salt, talc or mineral oil. The lubricating mixture isthen compressed into tablets. A protective coating consisting of asealing coat of shellac, a coating of sugar and methylcellulose, and apolish coating of carbauba wax may be provided.

Oral fluids are prepared in unit dosage forms such as syrups m I (\AAnoon and elixirs wherein each teaspoonful of composition contains apredetermined amount of the compound for administration.

The pharmacological properties of the 3-phenyl-5-alkylhydantoin ofFormula 11 can be conveniently observed in standard and accepted tests,which are recognized by pharmacologists as correlating to a specifictherapeutic response. For example, antiinflammatory activity can bereadily observed in the anticarrageenin study, which is generallyperformed in the rat and in other conventional tests using otherspecies. Antipyretic effects can be observed in rats fevered by Brewersyeast as well as in canines fevered by vaccine. Thus in the latter test,a highly significant antipyretic effect is observed at a dose of 200mg/kg.

In terms of analgesic effect, the compounds are comparable to aspirin.The antiinflammatory, analgesic and antipyretic activities of the3-phenyl-5-alkylhydantoins of Formula 11 are all observed in a dosagerange of from about to about 500 mg/kg of body weight; preferably fromabout to about 250 mg/kg, the precise dosage depending upon the nature,age and size of the species, the particular indication involved and theresponse observed.

The following examples will serve to further typify the nature of thisinvention but should not be construed as a limitation thereof.

EXAMPLE 1 p-Fluorophenylisocyanate (0.12 mole, 16.48 g) is added to asuspension of D,L-alanine methyl ester hydrochloride (0.12 mole, 16.74g) and sodium bicarbonate (0.12 mole, 10.08 g) in anhydrous benzene (120ml). The reaction mixture is heated at reflux for 5 hours and thencooled. The reaction mixture is filtered and the collected solid iswashed well with water to remove salts and dried; m.p. l5568. A solutionof this material, consisting essentially of N -(p-fluorophenynN2-propionic acid methyl ester)urea, in 3N hydrochloric acid (150 m1) andethanol (150 ml) is heated at reflux for 4 hours. The reaction mixtureis cooled and the 3-(p-fluorophenyl)-5- methylhydantoin is collected byfiltration and further purified through a preliminary recrystallizationfrom ethanol and three recrystallizations from isopropanol with charcoalclarification. The purified material demonstrates a melting point of1831 8 6 C. and a A of 215 p. with a shoulder at 26011,. A typicalcarbonhydrogen analysis is as follows:

Calcd. for C H F O C, 57.68; H, 4.36; N, 13.46; Found: 57.39; 4.36;13.22.

EXAMPLE 2 To a suspension of D,L-alanine methyl ester hydrochloride(0.13 mole, 18.09 g) and sodium bicarbonate (0.13 mole, 10.94 g) inanhydrous benzene (130 mole, 19.3 g). This mixture is heated at refluxfor 10 hours and then cooled. The product is collected by filtration,washed with water and recrystallized twice from methanol (200 ml) andonce from ethanol. This material is dissolved in boiling 6N sodiumhydroxide solution (165 ml) and the insoluble material is removed byfiltration of the hot solution through a glass sintered funnel. Thefiltrate is cooled and the sodium salt which precipitates is collectedby filtration, washed with 6N sodium hydroxide solution and redissolvedin water. This solution is adjusted to pH 4 with 50 percent acetic acidand 5-)p-'methoxyphenyl)-2-methylhydantoic acid, m.p. 176-177 C.precipitates. A suspension ofthis acid in ethanol (1 10 ml) and 1Nhydrochloric acid (110 ml) is heated at reflux for four hours and cooledto yield the product, 3-(p-(p-methoxyphenyl)-5-methylhydantoin, whichafter one recrystallization from ethanol melts at 179180 C. Thefollowing is a typical analysis:

Calcd. for C,,H,,N,0,= C, 59.99; H, 5.49; N, 12.72; Found: 59.74; 5.52;12.67

EXAMPLE 3 m-Trifluoromethylphenylisocyanate (0.09 mole, 16.8 g), inD,L-alanine methyl ester hydrochloride (0.09 mole, 12.4 g), and sodiumbicarbonate (0.09 mole, 7.56 g) in anhydrous benzene ml) is heated atreflux for 5 hours and cooled. The reaction mixture is filtered and thecollected solid is washed with water. Themother liquor is evaporated todryness and the residue is dissolved in chloroform and water. Theorganic phase is separated, dried over sodium sulfate and evaporated todryness to yield N -(m-trifluoromethylphenyl N -(2-propionic acid methylester)urea as an oil.

A solution of this oil is 3N hydrochloric acid (1 12.5 ml) is heated atreflux for 4 hours and then cooled. The product is collected byfiltration and the mother liquor is refiltered to give a second crop.The combined solid is suspended in ether and stirred at room temperatureand filtered. 3-(m- Trifluoromethylphenyl)-5-methylhydantoin, m.p.135-137 C., is thus collected and further purified throughrecrystallization from benzene. A typical analysis is as follows:

Calcd for Found: 50.99;

In a similar fashion utilizing p-trifluoromethylphenylisocyanate thereis obtained 3-(p-trifluoromethylphenyl)-5- methylhydantoin, m.p. 1801 81C.

EXAMPLE 4 EXAMPLE 5 p-Fluorophenylisocyanate (0.1685 mole, 23.05 g) isadded dropwise over a 10 minute period to a mixture of L-alanine (0.1685mole, 15 g) and potassium hydroxide (0.1685 mole, 9.44 g) in water (1432m1) at 5 to 10 C. The mixture is stirred with cooling at 5 to 10 C. for3 hours and filtered. The filtrate is cooled and rendered acidic (pH1-2) with concentrated hydrochloric acid. Water (83.2 ml) andisopropanol (33.7 ml) are added and the mixture is heated at C. for 2hours, cooled and filtered. The crude product is dissolved in chloroform(1,000 ml), washed with saturated sodium bicarbonate solution and thenwith water. The chloroform solution is dried over sodium sulfate andevaporated to dryness to yield L-3-(p-fluorophenyl)-5-methylhydantoin,m.p. 134l36 C., which is recrystallized from isopropanol, m.p. 139140 C.Optical rotation (1 percent methanol solution at 25C.)

a D observed rotation wave length -38.80.388 589 mp. -40.80.408 57846.4-0.464 546 80.80.808 436 132.41.324 365 Utilizing D-alanine in placeof L-alanine, there is obtained D-3-(p-fluorophenyl)-5-methylhydantoin,m.p. 139140 C. Optical Rotation (1 percent methanol solution at 25C.)

a D observed rotation wave length 39.50.395 589 m 40.90.409 57846.90.469 549 82.10.821 436 EXAMPLE 6 p-Fluorophenylisocyanate (0.11mole, 15.3 g) is added to D,L norleucine methyl ester hydrochloride (0.11 mole, 20 g) and sodium bicarbonate (0.11 mole, 9.24 g) in anhydrousbenzene ml). The mixture is heated at reflux for 5 hours,

cooled and filtered, the solid being washed with benzene. The filtrateis evaporated to dryness and the residue is combined with the solid andheated at reflux for 4 hours in 3N hydrochloric acid (110 ml) and 28ethanol (1 ml). The solution is cooled and filtered and the product iswashed with water and dissolved in chloroform (220 ml). This solution iswashed with saturated sodium bicarbonate solution, dried over sodiumsulfate and evaporated to dryness to give3-(pfluorophenyl)-5-butyl-hydantoin, m.p. l34-136 C. which isrecrystallized from isopropanol (75 ml), m.p. l34-l 36 C.

EXAMPLE 7 Ingredient Quantity/capsule3-(pChlorophenyl)-5-methylhydantoin 00 mg Corn Starch U.S.P. 200 mg Theforegoing ingredients are mixed and introduced into a two piece No. 1hard gelatin capsule.

A similar formulation is employed for a capsule composition utilizing3-( p-l'luorophenyl)-S-methylhydantoin.

EXAMPLE 8 Ingredient Quantity/tablet 3(p-methylphenyl)-5-methylhydantoin50 mg Corn starch U.S.P. 130 mg Lactose 160 mg Cab-O-Sil M-5 4 mgGelatin U.S.P. 5 mg Magnesium Stearate U.S.P. 1 mg The foregoingingredients are thoroughly mixed and pressed into tablets suitable fororal administration of 50 mg of active ingredient. The tablets may bescored to permit administration of fractional closes.

EXAMPLE 9 Ingredient Quantity/tablet3-(p-Methoxyphenyl)-5-methylhydantoin 250 mg Lactose mg Corn Starch 70mg Soluble starch 15 mg Magnesium stearate 5 mg The first threeingredients are thoroughly mixed and granulated with a solution of thesoluble starch. This granulate is dried, mixed with the magnesiumstearate and pressed into tablet cores which are coated as with sugar.

What is claimed is:

l. A compound of the formula

2. A compound according to claim 1 where R1 is p-fluoro.
 3. A compoundaccording to claim 1 which is 3-(p-fluorophenyl)-5-methylhydantoin.
 4. Acompound according to claim 1 which is3-(p-methoxyphenyl)-5-methylhydantoin.
 5. A compound according to claim1 which is 3-(p-trifluoromethylphenyl)-5-methylhydantoin.
 6. A compoundaccording to claim 1 which is 3-(p-fluorophenyl)-5-butylhydantoin.